Aliphatic polyesters have recently been attracting much attention from the environmental point of view for their gradual degradability by climate or biological environment into non-toxic degradation products when left in natural environment. Aliphatic polyesters have also been a subject of many researches in medical field, as bioabsorbable materials. As a typical aliphatic polyester, polylactide is known.
Polylactide has a melting point of as high as 173° C. and excellent mechanical strength, but, on the other hand, its high crystallinity results in rigid property (314 Kpsi) and lack of flexibility and water absorbability. Such properties of polylactide limit its application mainly to medical joint and screws for bones or the like, or plates. In order to overcome such disadvantages, block copolymers of aliphatic polyester and flexible polyalkylene glycol are proposed in Non-patent Publications 1 to 5 and other publications. However, there has been no discussion made to date about random copolymerization of polylactide and polydepsipeptide.
Even block copolymers of polyethylene glycol (PEG) and polylactide that are available from the researches to date, have not given biocompatible materials that could stand for clinical use. For achieving sufficient flexibility and water absorbability, the polymerization degree of polylactide must be reduced, which inevitably lowers the mechanical strength and results in severely limited applications. On the other hand, if the polymerization degree of polylactide is increased, the bioabsorbability of the resulting copolymer is lowered, and flexibility and water absorbability can no longer be expected. Thus the copolymer cannot sufficiently exhibit functions as a biocompatible material.
Patent Publication 1 discloses to add PEG having a molecular weight of not lower than 2000 as a third component to a copolymer of polylactide and polyalkylene ether, such as PEG, which is a hydrophilic polymer. This publication, however, discloses merely a blend with a plasticizer, and does not disclose copolymerization with amino acid. The technical point of this example is to blend PEG as a plasticizer, which achieves improvement in rigidity compared to polylactic acid alone, but is not expected to achieve elasticity like living tissues. In addition, the plasticizer (PEG), which leaks in water, has limited in vivo applications.
Patent Publication 2 discloses an A-B-A triblock copolymer of PEG and aliphatic polyester polycaprolactone as an injectable polymer for drug delivery that is degradable in living organisms. This solution, however, disperses in water, and naturally mechanical strength cannot be expected. This publication is silent about a copolymer of PEG and polylactide, polyglutamic acid, or polyaspartic acid as a hydrophobic segment.
Patent Publication 3 discloses a polylactic acid block copolymer having an amide bond. However, this copolymer is not expected, from its molecular structure, to have absorbability and flexibility sufficient for a biocompatible material.
Non-patent Publications 6 and 7 report on copolymerization of depsipeptide and lactide. However, this copolymerization aims at introduction of functional groups into lactide, and sufficient water absorbability and flexibility cannot be expected in the copolymer per se. A triblock copolymer of PEG and a random copolymer of lactide and depsipeptide, or an A-B-A block copolymer of PEG and depsipeptide is not known.
Patent Publications 4 to 6 disclose reverse thermal sensitivity and various applications, such as preparation for sustained drug delivery, of a block copolymer of PEG and polylactide. However, the PEG constituting this copolymer has a molecular weight of 500 to 10000, so that both the mechanical strength and the moisture retaining ability of the gel can hardly be met at the same time. On the other hand, when the compositional ratio of polylactide is increased to achieve sufficient gel strength, other problems will arise, such as reduced biodegradability, due to the crystallinity of polylactide, and thus the material can no longer be used as a biocompatible material.
Patent Publication 1: JP-8-199052-A
Patent Publication 2: JP-8-176016-A
Patent Publication 3: JP-11-302374-A
Patent Publication 4: JP-2002-533377-T
Patent Publication 5: JP-2002-519333-T
Patent Publication 6: JP-2002-516910-T
Non-patent Publication 1: Y. Kimura, et al., Polymer 30, p1342 (1989)
Non-patent Publication 2: X. M. Deng, et al., J. Polym. Sci. Polym. Lett., 28, p 411 (1990)
Non-patent Publication 3: K. J. Zhu, et al., J. Appl. Polym. Sci., 39, p 1 (1990)
Non-patent Publication 4: H. R. Kricheldorf, et al., Makromol. Chem., 194, p 463 (1993)
Non-patent Publication 5: S. M. Li, et al., Macromolecules, 29, p 57 (1996)
Non-patent Publication 6: T. Ouchi, et al., J. Polym. part A: Poly. Chem., 35, p 377-383 (1997)
Non-patent Publication 7: G. John, et al., J. Polym. Sci. Part A: Polym. Chem., 35, p 1901-1907 (1997)